Compositions for the treatment of dandruff

ABSTRACT

Seborrheic dermatitis of the scalp is treated by a synergistic combination of a cytotoxic agent and an antifungal agent.

This is a 371 of PCT/US96/03988 filed Mar. 20, 1996.

FIELD OF THE INVENTION

The invention relates to pharmaceutical compositions for use in thetreatment of seborrheic dermatitis of the scalp.

BACKGROUND OF THE INVENTION

Dandruff, seborrheic dermatitis of the scalp, is a common diseaseinvolving 3-5% of the population. Dandruff is, in many cases, theprecursor of alopecia (baldness) and constitutes a chronic and almostintractable cosmetical and social inconvenience. The pathophysiology ofthe disease remains unknown, although it is known to involve ahyperproliferative state of the skin, a limited inflammatory process,and a secondary microbial colonization by the lipophilic yeastPityrosporum, which is abundant and significantly overpopulated on thescalp of seborrheic patients.

Dandruff is a chronic and almost incurable disease. Available treatmentsresult only in short term effects with an eventual recurrence of thedisease.

A traditional treatment of dandruff included administration onto thescalp of either a cytotoxic agent or an antifungal agent. However, aspointed out heretofore no treatment provides long term alleviation fromthe symptoms of this disease.

It is an object of the invention to provide a composition useful in thetreatment of dandruff or symptoms associated therewith.

It is another object of the invention to provide a method foralleviation of dandruff or symptoms associated therewith.

GENERAL DESCRIPTION OF THE INVENTION

The present invention provides by a first of its aspects a composition,e.g. in the form of a hair shampoo, for the treatment of dandruff or ofsymptoms associated therewith, comprising in combination an effectiveamount of at least one cytotoxic agent and an effective amount of atleast one antifungal agent, together with a carrier, a diluent or anexcipient.

The term "effective amount" as used herein means to denote an amount ofan agent effective in achieving a therapeutic result in the treatment ofdandruff, such as alleviation of itching, a decrease in the amount ofscales, a reduction in the rate of hair loss, a reduction in scalpredness, etc.

The term "cytotoxic agent" as used herein means to denote an agent whichinhibits proliferation of keratinocytes skin cells. The term "antifungalagent" will be used to denote an agent which is specifically active ininhibiting growth of fungus and the fungus' ability to colonize theskin, which includes, intei alia, agents which are destructive to fungi,or active in suppressing growth of fungus or affect their ability toreproduce.

It will be appreciated by the artisan that the agents which arecytotoxic may also have some anti-fungal activity and an anti-fungalagent may also have somc cytotoxic activity. Thus, the term "cytotoxicagent" refers to agents which are known in the art primarily by havingcytotoxic activity and the term "antifungal agent" refers to agentswhich are known in the art primarily by their antifungal activity.

In the following description reference will at times be made toconcentrations given in percent (%), this indication meaning the numberof weight units of any ingredient in hundred weight units of an entirecomposition.

Examples of cytotoxic agents useful in accordance with the invention arecoal tars, zinc pyrithione or the like. The preferred cytoxic agent iscoal tar, typically included in the composition in concentration of1-5%.

Examples of antifungal agents useful in accordance with the inventioninclude imidazoles, ciclopiroxolamines and metronidazoles. Theimidazoles, which are preferred in accordance with the invention,include ketoconozole, bifonazole, itraconazole, econazole, clotrimazole,miconazole, oxiconazole, isoconazole and the like. From the imidazoles,ketoconozole is particularly preferred. Typically, the antifungal agentis included in the composition in a concentration of 0.5-5%.

The present invention further provides the use of said cytotoxic agentin combination with said antifungal agent for the preparation of acomposition, e.g. a medical hair shampoo, for the treatment of dandruff.

A further aspect of the invention is concerned with the treatment ofindividuals suffering from dandruff by combined application to the scalpof such individuals of said cytotoxic agent and of said antifungalagent. The individuals may be treated by the use of a singlecomposition, e.g. in the form of a hair shampoo, comprising both agents.Alternatively, the individuals may be treated by a combination of twodifferent compositions, one comprising said cytotoxic agent and theother said antifungal agent.

The above described combination may be applied 3-4 times during thefirst week from the start of the treatment, and 1-2 times a week,thereafter.

The present invention also pertains to a package comprising at least twocompositions, one comprising said antifungal agent and the other saidcytotoxic agent, optionally with instructions for use in said method.

In the following the invention will be illustrated with reference to anon-limiting specific embodiment described in the Example below.

EXAMPLE 1

A group of six patients (ages 17-38) with a severe case of dandruff wereon a regular bi-weekly anti seborrheic treatment prior to the onset ofthe experiment. During the experiment they were treated with acombination of the following two compositions:

a. a composition comprising 1.8% coal tar

b. a solution comprising 2% ketoconazole.

The patients were instructed to apply the two compositions, one afterthe other, in an amount sufficient to cover the entire scalp. Thepatients were instructed to apply the compositions on days 1, 3, 6 and9. The patients' conditions were examined after 14 or 30 days followingthe onset of treatment.

The patients' conditions were evaluated by the following criteria:

(i) scaling--existence of scales on the scalp, typically at the temporalarea;

(ii) itching--based on the patient's subjective feeling;

(iii) severity--overall assessment of the dandruff disease situation,taking into account the skin redness as an indication of inflammatoryconditions.

For the above criteria a score was given by using the following scale:

0--non existing

1--minimal

2--moderate

3--severe

The results are shown in the following Table 1:

                  TABLE 1                                                         ______________________________________                                        Patient         Scale     Itch    Severity                                    No.   Age    Sex    B*   A.sup.+                                                                            B*   A.sup.+                                                                            B*   A.sup.+                                                                            Day                         ______________________________________                                        1     22     m      2    0    2    0    2    0    30                          2     38     m      3    1    3    0    3    1    14                          3     23     m      2    0    2    0    2    0    14                          4     27     m      2    0    2    0    2    0    14                          5     17     f      3    1    3    1    3    1    14                          6     37     m      2    0    2    0    2    0    14,30                       ______________________________________                                         *B  before treatment according to the present invention;                      .sup.+ A  after treatment.                                               

The results of Table 1 showt clearly that following treatment, there isa considerable decrease in scale formation, reduction in scalp rednessand itching in all treated patients. The subjects reported that theimprovements started within about five days from the onset of thetreatment. Furthermore, this combined treatment brought to a remissionof the disease's symptoms for about two weeks in some of the patients,after the treatment was terminated, as can be seen in the patientstested after thirty days.

EXAMPLE 2

A group of three patients who had no record of treatment for dandruffprior to the onset of the experiment, was given the same treatment as inExample 1. The patients' condition was as severe as in Example 1.

The results are shown in the following Table 2:

                  TABLE 2                                                         ______________________________________                                        Patient         Scale     Itch    Severity                                    No.   Age    Sex    B*   A.sup.+                                                                            B*   A.sup.+                                                                            B*   A.sup.+                                                                            Day                         ______________________________________                                        1     32     f      1    0    1    0    1    0    30                          2     27     f      2    1    3    1    2    1    30                          3     24     f      1    0    1    0    1    0    14                          ______________________________________                                         *B  before treatment according to the present invention;                      .sup.+ A  after treatment.                                               

Again it is clearly demonstrated that the combined application of thetwo compositions, results in a substantial disappearance of the symptomsaccompanying dandruff disease.

What is claimed is:
 1. A composition for topical treatment of seborrheicdermatitis of the scalp comprising at least one cytotoxic agent and atleast on antifungal agent in respective amounts sufficient to achieve asynergistic result in said treatment, said composition furthercomprising a carrier, a diluent or an excipient.
 2. The compositionaccording to claim 1 wherein the cytotoxic agent is selected from thegroup consisting of coal tar and zinc pyrithione, and the antifungalagent is an antifungal imidazole.
 3. The composition according to claim2, wherein the antifungal agent is selected from the group consisting ofketoconazole and bifonazole.
 4. The composition according to claim 3,wherein the cytotoxic agent is coal tar.
 5. The composition according toclaim 1, wherein the cytotoxic agent is zinc pyrithione and theantifungal agent is ketoconazole.
 6. The composition according to claim1, wherein the cytotoxic agent is selected from the group consisting ofcoal tar and zinc pyrithione.
 7. The composition according to claim 6,comprising 1 to 5% of said cytotoxic agent.
 8. The composition accordingto claim 6, wherein the antifungal agent is selected from the groupconsisting of imidazoles and ciclopiroxolamines.
 9. The compositionaccording to claim 8, wherein the antifungal agent is selected from thegroup consisting of ketoconazole, bifonazole, itraconazole, econazole,clotrimazole, miconazole, oxiconazole and isoconazole.
 10. Thecomposition according to claim 8, comprising 0.5 to 5% of saidantifungal agent.
 11. A method for treatment of seborrheic dermatitis ofthe scalp of a user comprising applying to the scalp at least onecytotoxic agent in combination with at least one antifungal agent inrespective amounts sufficient to achieve a synergistic result in saidtreatment.
 12. The method according to claim 11, wherein the cytotoxicagent is selected from the group consisting of coal tar and zincpyrithione, and the antifungal agent is an antifungal imidazole.
 13. Themethod according to claim 12, wherein the antifungal agent is selectedfrom the group consisting of ketoconazole and bifonazole.
 14. The methodaccording to claim 13, wherein the cytotoxic agent is coal tar.
 15. Themethod according to claim 12, wherein the cytotoxic agent is zincpyrithione and the antifungal agent is ketoconazole.